The invention is concerned with new derivatives of 1-styrene-sulphonyl-2-oxo-5-hydroxy pyrrolidine, the process and the intermediates for their preparation, their use as medicaments and compositions containing them.
The invention relates to compounds of the general formulas (I): ##STR2## in which R.sub.1 represents a linear or branched alkyl radical, containing up to 8 carbon atoms, an acyl radical containing from 1 to 6 carbon atoms or a cycloalkyl radical containing from 3 to 6 carbon atoms and R represents an aryl radical containing up to 14 carbon atoms, possibly substituted, or a heterocyclic radical, mono- or polycyclic, possibly substituted.
The invention includes the compounds with the formula (I) in which the geometry of the double bond is trans or cis, as well as mixtures of these products with trans and cis geometry.
By alkyl radical, there is preferably meant an alkyl radical containing from 1 to 5 carbon atoms, for example, a methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tertbutyl or n-pentyl radical.
By acyl radical, there is preferably meant an acetyl, propionyl or butyryl radical.
By cycloalkyl radical, there is preferably meant a cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl radical.
By aryl radical, there is preferably meant a phenyl or naphthyl radical.
By heterocyclic radical, there is preferably meant one of the following radicals; furyl, thienyl, pyranyl, pyridyl, benzofuranyl, isobenzofuranyl, chromanyl, isochromanyl, chromenyl, xanthenyl, phenoxathienyl, oxazolyl, isoxazolyl, furazanyl, phenoxazinyl, thieno(2,3-b)furanyl, 2H-furo(3,2-b)pyranyl, benzoxazolyl or morpholinyl.
When the radical R is substituted, it is preferably carries as substituents one or more substituents selected from the group consisting of the free, esterified or etherified hydroxyl radicals, in which the ester or ether part contains from 1 to 18 carbon atoms, such, for example as the acetoxy radical, the methoxy radical or the benzyloxy radical; the radical ##STR3## in which R.sup.1 represents an alkyl radical containing 1 to 8 carbon atoms; the linear, branched or cyclized, saturated or unsaturated alkyl radicals, containing up to 18 carbon atoms, such, for example, as the methyl, ethyl, propyl or isopropyl radical; the ethenyl radical, or the ethynyl radical; the halogen atoms, such as fluorine, chlorine, bromine; the CF.sub.3, SCF.sub.3, OCF.sub.3, NO.sub.2, NH.sub.2 or C.tbd.N groups; and the phenyl radical.
The invention particularly relates to the compounds of the formula (I) in which R represents a phenyl radical possibly substituted by an alkoxy radical containing up to 4 carbon atoms, such, for example as the methoxy radical.
More particularly, the invention has as its object the compounds with the formula (I) in which R.sub.1 represents an ethyl radical.
Even more particularly an object of the invention are the products of the examples.
The compounds of the invention possess useful pharmacological properties; they retard the extinction of a conditioned avoidance response, they retard the disappearance of a learned response and they benefit attention, vigilance and memorization.
Therefore, the products with the formula (I) are useful in particular in the treatment of intellectual or nervous asthenias, memory failures, old age and excessive intellectual fatigue.
The invention has more particularly, as an object as a medicament, the product of Example 1.
The usual posology is variable according to the affection concerned, the subject treated and the administration route, it can be between 50 mg and 3000 mg per day, preferably from 100 to 600 mg, for example between 150 and 1500 mg per day, preferably between 100 and 200 mg, in one or more doses for the product of Example 1 administered by oral route.
The present invention also relates to the pharmaceutical compositions containing as the active principle at least one compound with the formula (I). The pharmaceutical compositions of the invention can be solid or liquid and are presented in the pharmaceutical forms currently use in human medicine, such, for example, as plain or sugar-coated tablets, capsules, granules, suppositories or injectable preparations; they are prepared according to the usual methods.
The active principle or principles can be incorporated with the excipients usually employed in these pharmaceutical compositions, such as talc, gum arabic, lactose, starch, magnesium stearate, cocoa butter, aqueous or non-aqueous vehicles, fatty substances of animal or vegetable origin, paraffin derivatives, glycols, various wetting, dispersing or emulsifying agents and preservatives.
The invention also has as its object a process for the preparation of the compounds with the formula (I) characterized in that a compound with the formula (II): ##STR4## in which R.sub.1 has the same significance as discussed previously, is submitted to the action of a compound with the formula (III): EQU RCH.dbd.CH--SO.sub.2 Hal (III)
in which Hal represents a chlorine or bromine atom and R has the same significance as discussed previously, in order to obtain the corresponding compound with the formula (I).
In a preferred way of carrying out the process of the invention, the reaction between the product with the formula (II) and the product with the formula (III) is effectuated:
(a) in the presence of a strong base such as butyllithium or an alkaline hydride, such as sodium hydride,
(b) in a solvent chosen from the group constituted by tetrahydrofuran, benzene, dimethylformamide, dimethylsulphoxide, the monoethyl ether of diethylene glycol and the diethyl ether of diethylene glycol.
The products with the formula (II) used as starting products are products known in a general way, and they can be prepared according to the processes described in TETRAHEDRON 31, 1437 (1975), TETRAHEDRON 41, 2007 (1985) or in SYNTHESIS (4) 315-17 (1980).
The 5-n-propyloxy pyrrolidine-2-one and the 5-isopropyloxy pyrrolidine-2-one, however, are new products and are themselves one of the subjects of the present invention.
The products with the formnula (III), used as starting products are known in a general way; they can be prepared according to the process described in CA 47 3262c (1953).
The 4-methoxystyrene sulphonyl chloride is, however, a new product and is, therefore for this reason, a subject of the present invention.